PROJECT SUMMARY/ABSTRACT Advancements in human genetics now poise the field to illuminate the pathophysiology of inflammatory pathologies and infectious disease. Although the mechanisms of immune-mediated tissue homeostasis are incompletely understood, genetic analyses of inflammatory disease and primary immunodeficiencies have implicated shared proteins and pathways representing key immune checkpoints. Efforts to map the genetic architecture of inflammatory bowel disease (IBD) have been particularly fruitful, leading to the discovery of ATG16L1 T300A, which revealed the importance of autophagy in innate immunity. We have since shown that the ATG16L1 T300A allele conspires with environmental triggers to induce several cell type-specific phenotypes resulting in tissue dys-homeostasis and predisposition to inflammatory pathology. Thus, mechanistic characterization of a pathogenic autophagy variant has provided fundamental insights into mucosal immunity. The focus of this application is to understand how genetic perturbation of autophagy checkpoints impacts inflammation control and tissue homeostasis in the context of mucosal immunity. Towards this end, we propose to: (1) Define the role of autophagy checkpoints in intestinal inflammation, (2) Identify the molecular mechanisms by which autophagy controls antigen presentation and tissue homeostasis, and (3) Perform a comprehensive genetic dissection of the Inflammation-Autophagy link.